Vascular interventions, including angioplasty, stenting, atherectomy and grafting are often complicated by undesirable effects. Exposure to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions. For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels. Similarly, the implantation of urinary catheters can cause infections, particularly in the urinary tract. Other adverse reactions to vascular intervention include endothelial and smooth muscle cell proliferation which can lead to hyperplasia, restenosis i.e. the re-occlusion of the artery, occlusion of blood vessels, platelet aggregation, and calcification. Treatment of restenosis often involves a second angioplasty or bypass surgery. In particular, restenosis may be due to endothelial cell injury caused by the vascular intervention in treating a restenosis. The drawbacks of such treatment, including the risk of repeat restenosis, are obvious.
For example, angioplasty involves insertion of a balloon catheter into an artery at the site of a partially obstructive atherosclerotic lesion. Inflation of the balloon is intended to rupture the intima and dilate the obstruction. About 20 to 30% of obstructions reocclude in just a few days or weeks. Eltchaninoff et al., Balloon Angioplasty For In-Stent Restenosis, 1998, J. Am Coll. Cardiol. 32(4): 980-984. Use of stents reduces the re-occlusion rate, however a significant percentage continues to result in restenosis. The rate of stenosis after angioplasty is dependent upon a number of factors including the length of the plaque. Stenosis rates vary from 10% to 35% depending the risk factors present. Further, repeat angiography one year later reveals an apparently normal lumen in only about 30% of vessels having undergone the procedure.
Restenosis is caused by an accumulation of extracellular matrix containing collagen and proteoglycans in association with smooth muscle cells which is found in both the atheroma and the arterial hyperplastic lesion after balloon injury or clinical angioplasty. Some of the delay in luminal narrowing with respect to smooth muscle cell proliferation may result from the continuing elaboration of matrix materials by neointimal smooth muscle cells. Various mediators may alter matrix synthesis by smooth muscle cells in vivo. A “cascade mechanism” has been proposed for restenosis. In this model, an injurious stimulus induces expression of growth-stimulatory cytokines such as interleukin 1 and tumor necrosis factor. Libby et al., Cascade Model of Restenosis 1992, Circulation 86(6): III-47-III52.
Various therapies have been attempted to treat or prevent restenosis. For example, it has been reported that, since oxidizing metabolites may induce chain reactions that may lead to restenosis, multivitamins having antioxidant properties (30,000 IU of beta carotene, 500 mg of vitamin C and 700 IU of vitamin E) and/or probucol (500 mg) were studied. They were administered twice daily for four weeks prior and six months after angioplasty, Tardif et al., 1997, N. Engl. J. Med. 337(6): 365-72. The antioxidant vitamins alone had no effect. Probucol did reduce the rate of restenosis after angioplasty by almost 50%. However, probucol has been removed from the U.S. market for reducing HDL cholesterol levels, and causing heart rhythm disturbances which might lead to dangerous arrhythmias.
Other therapies for treatment or prevention of restenosis that are under exploration include radiation (both β and γ emitters) delivery stents. Intracoronary irradiation during angioplasty and stent implantation to reduce the instances of restenosis have been studied. Limitations include, for example, handling stents filled with radioactive liquid (Re 188-radioactive rhenium). Further, studies show that this strategy may need to be tailored to stent design for proper distribution for the absorption and scattering of beta emitters. Amols et al., 1998, Circulation 98:2024-2029. Recently developed radiation delivery stents work on delivering radiation precisely at the location of stent deployment, either by placing a radioactive stent or by a secondary procedure of radiation delivery within the lumen of the stent following stent placement. This secondary procedure is usually carried out by placing a radioactive wire or a tube with radioactive seeds precisely within the stent and along the length of the stent. The radiation dose is administered such that it affects only the vessel wall. The treatment of restenosis with radiation has been shown to be effective although significant side effects have been observed, including late thrombosis, medial thinning and advential fibrosis.
Other methods for treatment or prevention of restenosis, include the administration of pharmaceuticals, such as anticoagulants and antibiotics, in or on medical devices, through systemic or local infusion. Various efforts and many state-of-the art stents that are undergoing clinical trials focus on the treatment of restenosis following stent placement. Drug delivery stents attempt to reduce restenosis by administering anti-inflammation drugs and cytotoxic drugs, which are used to prevent hyperplasia. Hormones may be delivered to control vessel hyperplasia near the stent. In many cases, anti-platelet or other anti-thrombotic agents may be incorporated to prevent thrombosis within the lumen of the stent.
In addition, gene therapy or protein therapy can be used for treatment or prevention of restenosis, cancer or hyperplasia through the administration of a biologically active material, such as nucleic acid or protein, to a subject who has restenosis, cancer or hyperplasia in whom prevention or inhibition of restenosis, cancer or hyperplasia is desirable. Genes expressing either cytotoxic or cytostatic proteins have been used. The major limitation in this approach has been the difficulty in getting enough of the gene into the afflicted tissue. Adenoviral vectors have improved the delivery of genes to tissues but only moderately.
For general reviews of the methods of gene therapy, see Goldspiel et al., 1993, Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann. Rev. Biochem. 62:191-217; May, 1993, TIBTECH 11(5):155-215). Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), 1993, Current Protocols in Molecular Biology, John Wiley & Sons, NY; Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY; and in Chapters 12 and 13, Dracopoli et al. (eds.), 1994, Current Protocols in Human Genetics, John Wiley & Sons, NY.
One of the problems with the current technology, in particular radioactive stents, is that restenosis may still occur at the parts of the surface of the body lumen that are in contact with the ends of a stent. Closure or constriction of the vessels commonly occurs when the vascular cells proliferate around the ends of the stent. This is known as the “candy-wrapper effect”, also known as edge restenosis or edge effect. Albiero et al., 2000, J. Invas. Cardiol. 12(8):416-421; Latchem et al., 2000, Catheter Cardiovasc Interv. 51(4):422-429; Kim et al., 2001, J. Am. Coll. Cardiol. 37(4):1026-1030. A schematic diagram describing this effect is show in FIG. 1. FIG. 1 shows a cross section of a body lumen with a radioactive stent implant where restenosis occurred at the opposing ends of the stent. The surface 10 of a body lumen 30 at the ends of the implanted stent 40 is surrounded by hyperproliferating tissues 20. This appearance is similar to a candy with a wrapper and thus the name “candy-wrapper effect”. A cause for some types of hyperplasia is that when a body lumen is treated with radiation, the radioactive source is usually targeted towards the center of the stent where the original lesion was situated. In an effort to minimize extraneous radiation to healthy vessel tissue, radiation is targeted towards the center. Hence, restenosis may still occur at the edge of the stent due to a lower dosage of radiation at the ends. The underlying mechanism for this effect is that the radiation dosage at the ends is at a level such that it stimulates cell growth as opposed to stopping it. Clearly, there remains a great need for therapies directed to the prevention and treatment of restenosis and related disorders.
Therefore, there is a need for a system to provide treatment of a body lumen particularly where it is in contact with the ends of a medical device such as a stent and in particular preventing intimal hyperplasia and smooth muscle cell proliferation which cause stenosis or restenosis of the body lumen.
Citation of references hereinabove shall not be construed as an admission that such references are prior art to the present invention.